Article

Toxic prefibrillar alpha-synuclein amyloid oligomers adopt a distinctive antiparallel beta-sheet structure.

Biochemical Journal (Impact Factor: 4.65). 01/2012;

ABSTRACT Parkinson's disease is an age-related movement disorder characterized by the presence in the mid-brain of amyloid deposits of the 140-aa protein alpha-synuclein (AS). AS fibrillation follows a nucleation polymerization pathway involving diverse transient prefibrillar species varying in size and morphology. Like for other neurodegenerative diseases, cytotoxicity is currently attributed to these prefibrillar species rather than to the insoluble aggregates. Nevertheless, the underlying molecular mechanisms responsible for cytotoxicity remain elusive and structural studies may contribute to the understanding of both amyloid aggregation mechanism and oligomer-induced toxicity. It is already recognized that soluble oligomeric AS species adopt beta-sheet structures that differ from those characterizing the fibrillar structure. In the present work we used ATR-FTIR spectroscopy, a technique especially sensitive to beta-sheet structure, to get deeper insight into the beta-sheet organization within oligomers and fibrils. Careful spectral analysis revealed that AS oligomers adopt an antiparallel beta-sheet structure whereas fibrils, a parallel arrangement. The data are discussed in terms of regions of the protein involved in the early beta-sheet interactions and the implications of such conformational arrangement for the pathogenicity associated to AS oligomers.

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